HYLS1

protein-coding

HYLS1 centriolar and ciliogenesis associated

Gene summary

This gene encodes a protein localized to the cytoplasm. Mutations in this gene are associated with hydrolethalus syndrome. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Oct 2008]

MANE transcript

NM_001134793.2

Inheritance

ClinVar variants

P:25U:65B:123

Top phenotype

Hydrolethalus syndrome

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr11:125,883,614-125,900,646

External References & Databases

Ensembl (ENSG00000198331)

Transcript & Mutation Effects

hg38 • Region Span ~17.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hydrolethalus syndrome 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009365

Submitter: Natera

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

hydrolethalus syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0006037

Submitter: Orphanet

hydrolethalus syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009365

Submitter: Labcorp Genetics (formerly Invitae)

hydrolethalus syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0006037

Submitter: ClinGen

HYLS1 was first reported in relation to autosomal recessive hydrolethalus in 2005 (Mee et al., PMID: 15843405). This is often a fatal fetal condition that results in stillbirth, or death shortly after birth. Prenatal features have been identified as early as the first trimester, and phenotypes include FGR (fetal growth restriction), brain anomalies, skeletal features (like femoral bowing and polydactyly/syndactyly), congenital heart disease, and genital anomalies. The most frequent features of this condition in probands with the founder missense mutation include hydrocephalus, small mandible, polydactyly, congenital heart defects, and respiratory anomalies. Affected probands compound heterozygous for the recurrent missense variant and another missense or nonsense variant have also been reported. Three variants (missense, nonsense) that have been reported in over 40 probands in 3 publications (PMIDs: 15843405, 18648327, 34212369) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. There were also two homozygous stop loss variants reported in 2 probands from 2 publications (PMID: 26830932, 36580738), but these were not scored because the phenotype does not fully match that of the other cases and and their disease mechanism similarity cannot be confirmed. This gene-disease relationship is also supported by experimental evidence (mouse model, drosophila model, expression-level data, interaction evidence, cell culture evidence, functional alteration evidence; PMIDs: 15843405, 19656802, 32509774, 40009365). Homozygous mutant mice exhibit perinatal lethality, brain anomaly, polydactyly, and kidney complications. The drosophila model showed ciliary dysfunction and atypical spermatogenesis in mutants. The gene is widely expressed in mice, including in specific brain regions such as the medulla. HYLS1 interacts with SAS-4 (CENPJ), which is definitively associated with autosomal recessive microcephaly 6 with/without short stature. Other experimental evidence indicates the key role of HYLS1 in centriole stability and ciliogenesis. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Prenatal GCEP on the meeting date 8/06/2025 (SOP Version 11).

hydrolethalus syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009365

Submitter: Genomics England PanelApp

hydrolethalus syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009365

Submitter: G2P

hydrolethalus syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009365

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hydrolethalus syndromeAR

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Pulmonary

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 7028327; 15843405; 18648327

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HYLS1 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 233

Inborn genetic diseasesTotal: 117

Hydrolethalus syndromeTotal: 55

Hydrolethalus syndrome 1Total: 30

Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndromeTotal: 17

not specifiedTotal: 11

PUS3-related disorderTotal: 10

HYLS1-related disordersTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001134793.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	119 clinvar	1 clinvar	122
missense	1 clinvar	1 clinvar	53 clinvar	2 clinvar	1 clinvar	58
nonsense		12 clinvar	4 clinvar			16
start loss			2 clinvar			2
frameshift	1 clinvar	10 clinvar	4 clinvar			15
splice donor/acceptor (+/-2bp)						0
Total	2	23	65	121	2	213

Highest pathogenic variant AF is 0.000621345

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001134793.2	RefSeq	NP_001128265.1	1	MANE Select
ENST00000425380.7	Ensembl	ENSP00000414884.2	1	MANE Select
NM_001377269.1	RefSeq	NP_001364198.1	1	Standard
NM_001377270.1	RefSeq	NP_001364199.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cilium assembly

Molecular Function

protein binding

Cellular Component

nucleus
cytoplasm
centrosome
centriole
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000425380
Coding exons: 1
Length: 17035
Individuals with no LoFs: 125675
Homozygous LoFs: 0
Heterozygous LoFs: 73
Defined: 125748
p: 0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.177	161	167	0.962	0.00000943	1932
Missense (PolyPhen)		50	60.806	0.82229		664
Synonymous	0.147	55	56.4	0.975	0.00000263	606
Loss of Function	0.298	14	15.3	0.918	0.00000118	136

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00066	0.00067	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00026	0.00026	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in ciliogenesis. {ECO:0000250|UniProtKB:A0A1L8ER70, ECO:0000250|UniProtKB:Q95X94}.;
Disease: DISEASE: Hydrolethalus syndrome 1 (HLS1) [MIM:236680]: A lethal syndrome characterized by polydactyly, central nervous system malformation, and hydrocephalus. The polydactyly is postaxial in the hands and preaxial in the feet. A highly characteristic hallux duplex is seen in almost no other situation. In half of the cases, a large atrioventricular communis defect of the heart is found. The pregnancy is characterized by hydramnios, which is often massive, and by preterm delivery. {ECO:0000269|PubMed:15843405}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in HYLS1 may be involved in ciliopathies other than hydrolethalus syndrome 1. A homozygous mutation resulting in a C-terminal extension of 11 residues has been found in patients diagnosed as Joubert syndrome, a ciliopathy presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:26830932}.;

Recessive Scores

pRec: 0.167

Intolerance Scores

LoFtool: 0.565
RVIS EVS: -0.03
RVIS percentile EVS: 51.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.752

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium